Abstract
Hydrogen sulfide (H2S) plays an important role in human physiology, exerting vasodilatory, neuromodulatory and anti-inflammatory effects. H2S has been implicated in the mechanism of gastrointestinal integrity but whether this gaseous mediator can affect hemorrhagic lesions induced by stress has been little elucidated. We studied the effect of the H2S precursor L-cysteine, H2S-donor NaHS, the H2S synthesizing enzyme (CSE) activity inhibitor- D,L-propargylglycine (PAG) and the gastric H2S production by CSE/CBS/3-MST activity in water immersion and restraint stress (WRS) ulcerogenesis and the accompanying changes in gastric blood flow (GBF). The role of endogenous prostaglandins (PGs) and sensory afferent nerves releasing calcitonin gene-related peptide (CGRP) in the mechanism of gastroprotection induced by H2S was examined in capsaicin-denervated rats and those pretreated with capsazepine to inhibit activity of vanilloid receptors (VR-1). Rats were pretreated with vehicle, NaHS, the donor of H2S and or L-cysteine, the H2S precursor, with or without the concurrent treatment with 1) nonselective (indomethacin) and selective cyclooxygenase (COX)-1 (SC-560) or COX-2 (rofecoxib) inhibitors. The expression of mRNA and protein for COX-1 and COX-2 were analyzed in gastric mucosa pretreated with NaHS with or without PAG. Both NaHS and L-cysteine dose-dependently attenuated severity of WRS-induced gastric lesions and significantly increased GBF. These effects were significantly reduced by pretreatment with PAG and capsaicin denervation. NaHS increased gastric H2S production via CSE/CBS but not 3-MST activity. Inhibition of COX-1 and COX-2 activity significantly diminished NaHS- and L-cysteine-induced protection and hyperemia. NaHS increased expression of COX-1, COX-2 mRNAs and proteins and raised CGRP mRNA expression. These effects of NaHS on COX-1 and COX-2 protein contents were reversed by PAG and capsaicin denervation. We conclude that H2S exerts gastroprotection against WRS-induced gastric lesions by the mechanism involving enhancement in gastric microcirculation mediated by endogenous PGs, sensory afferent nerves releasing CGRP and the activation of VR-1 receptors.
Highlights
Hydrogen sulfide (H2S) is a gaseous mediator, which plays an important role in human physiology [1]
We examined the mechanism of the potential protective action of H2S released from NaHS or that generated from its precursor L-cysteine against stress ulcerogenesis with special reference to endogenous prostaglandins (PGs) and sensory afferent nerves releasing calcitonin gene-related peptide (CGRP) by using animals with non-selectively and selectively inhibited COX-1 and COX-2 activity and those with functionally ablated sensory neurons by capsaicin, respectively [16, 17]
PAG alone administered in a dose of 30 mg/kg i.p. had no significant influence on water immersion and restraint stress (WRS) lesions, but reversed the decrease in lesion number and an increase in the gastric blood flow (GBF) induced by L-cysteine (10 mg/kg i.g.)
Summary
Hydrogen sulfide (H2S) is a gaseous mediator, which plays an important role in human physiology [1]. H2S is mostly generated via L-cysteine metabolism and the activity of two pyridoxal-5`-phosphate (P5P, vitamin B6) dependent enzymes: cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) [4, 5]. This molecule may be synthesized by another pathway, mainly within mitochondria, that involves the activity of 3-mercaptopyruvate sulfotransferase (3-MST) and cysteine aminotransferase [6]. The vasodilatory effects of the H2S donor, sodium hydrosulfide (NaHS) in blood vessels was confirmed by Kubo et al [9] and Zhao et al [10] who demonstrated that this donor results in a direct vasorelaxation of vascular smooth muscle acting as KATP channel opener
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